Blockade of the Sympathetic System in Hypertension & Heart ... fileAtelectasia Orthostatic...
Transcript of Blockade of the Sympathetic System in Hypertension & Heart ... fileAtelectasia Orthostatic...
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Blockade of the Sympathetic
System in Hypertension & Heart
Failure
Haralambos Gavras
Professor of Medicine
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Introduction
• Central sympatholytic agents are the oldest anti-
HTN drugs ( reserpine, methyldopa, clonidine ).
• Beta-AR blockers are now well established in
the treatment of HTN and HF.
• Recently two new approaches were introduced:
• Sympathetic denervation via renal nerve
ablation
• Selective blockade of the alpha 2B-AR subtype.
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Grimson, Ann Surg 1941
Surgical Sympathectomy
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Peet, Am J Surg 1948
BP control was maintained long-term
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Adverse effects of splanchnicectomy
Thoracic duct injuries
Atelectasia
Orthostatic hypotension and tachycardia
Palpitations
Breathlessness
Anhidrosis
Cold hands
Intestinal disturbances
Loss of ejaculation
Sexual dissatisfaction
Papademetriou/Dumas, Am J Cardiol 2010
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Renal Sympathetic Nerves as Therapeutic Target
• Arise from T10-L1• Follow the renal artery to the kidney• Primarily lie within the adventitia
Vessel Lumen
Media
Adventitia
Renal Nerves
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Results: Blood Pressure Reduction: Simplicity-1
-14 -21 -22 -24 -27-10 -10 -11 -11 -17
-50
-40
-30
-20
-10
0
10
1 month(n=41)
3 months(n=39)
6 months(n=26)
9 months(n=20)
12 months(n=9)
MeanChange in
Blood Pressure(mmHg)
Presented with 95% Confidence
Intervals
Systolic
Diastolic
* P<0.001
** P=0.02
*
* **
* * * *
* *
*
87% had a reduction
in SBP ≥ 10 mmHg
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Significant, Sustained BP ResponseExpanded series
92% of patients have BP ↓
-20 -24 -25 -24 -25 -33-10 -11 -11 -11 -15 -15
-50
-40
-30
-20
-10
0
10
1 M(n=138)
3 M(n=106)
6 M(n=82)
12 M(n=63)
18 M(n=32)
24 M(n=17)
Systolic
Diastolic
BP change(mmHg)
Schlaich et al. European Society of Hypertension. 2010.
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Approach
• Use of genetically engineered mice with
deletion of each one of the α2AR subtypes.
• Use of renoprival model of hypertension to
assess their roles in regulation of
cardiovascular function and sympathetic
outflow in response to salt loading.
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Indirectly Measured Mean Blood Pressure
α2A +/+
α2A -/-
α2B +/+
α2B +/-
α2C +/+
α2C -/-
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Conclusions
• Absence of α2A AR (leaving unopposed α2B AR activity) is associated with higher baseline BP and a more severe and rapid salt induced hypertension.
• Adequate expression of α2B AR is a prerequisite for development of salt induced hypertension.
• Because of the possibility that salt induced hypertension is partly a function of sodium reabsorption due to renal α2 AR, experiments were repeated in anephric mice.
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Role of the α2B AR subtype in acute
hypertensive response to hypertonic
saline infusion(I)
• Mice were initially subjected to right
nephrectomy.
– right iliac artery was catheterized for direct
pressure measurements
– right iliac vein was catheterized for saline infusion
• The following day the left kidney was removed.
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Role of the α2B AR subtype in acute
hypertensive response to hypertonic
saline infusion
• Arterial catheter was connected for direct
blood pressure measurements
• Venous catheter was connected to a
Harvard infusion pump containing 4%
saline.
– Total volume infused over 2 hours was 0.4ml
– 10% blood volume increase
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Mean arterial pressure during a 2 hour hypertonic saline
infusion in anephric mice: WT vs KO mice
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Conclusions
• Absence of fully functional α2B AR renders animals unable to raise BP in response to acute salt loading.
• Absence of α2A AR or α2C AR does not alter hypertensive response to acute salt overload in KO compared to WT animals.
• Taken together, the acute and chronic experiments suggest that central α2AAR attenuate and α2B ARaccentuate hypertensive response to salt loading, whereas α2C seems hemodynamically neutral.
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Gene treatment to block the expression
of the α2B adrenergic receptor in the
CNS
• Proposed Hypothesis:
– if the central α2B adrenergic receptor is
responsible for salt induced
hypertension, blocking its expression in the
CNS should prevent BP rise.
– confirm that α2B AR has a similar role in other
species.
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Inhibition of α2AR using Recombinant
AAV-delivered Antisense in
Hypertensive Rats
• Aim: Prolonged reversal of established salt
dependant hypertension in rats by using a
recombinant Adeno Associated Virus
vector for delivery of α2B AR AS-DNA.
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Inhibition of α2B AR using
Recombinant AAV-delivered Antisense
in Hypertensive Rats
• Wistar rats were subjected to subtotal nephrectomy and dietary salt loading.
• 2x1010 particles in a volume of 10-15µL Lipofectamine injected stereotaxically into the left lateral ventricle at a rate of 0.167µl/min, over 1-1.5hours.
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Scrambled-ODN treated rat
Antisense-ODN treated rat
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Pressure Recording Post Injection
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Conclusion
• Injection of AS-ODN against the α2BAR in
the CNS produces attenuation of blood
pressure rise.
– Translational inhibition of α2B AR centrally
prevents blood pressure rise.
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Summary
• An intact fully functional α2B AR is necessary
for the development of hypertension due to
salt loading .
• When unopposed as in the case of
α2A AR KO mice it causes a hypertensive and
hyperadrenergic state even at baseline.
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Summary
• The central presynaptic α2A AR is
sympathoinhibitory
• The central presynaptic α2B AR is
sympathoexcitatory